Funded Projects

The goal of this proposal is to conduct a randomized controlled trial to evaluate the comparative effectiveness of conservative behavioral and nonopioid pharmacological treatments (Phase I) and, among nonresponders, the benefits of nonsurgical procedural interventions (Phase II). Aim 1 will evaluate the effectiveness of individual and combined online cognitive behavioral therapy (painTRAINER) and pharmacologic treatment (duloxetine) in improving pain and function for knee osteoarthritis (KOA) patients compared with standard of care. Aim 2 will determine if genicular nerve radiofrequency ablation or intra-articular injection of hyaluronic acid and steroid is more effective in improving outcomes than local anesthetic nerve block or standard of care and help establish the role of these interventional treatments in the overall management of pain in KOA patients. Aim 3 will test whether clinical and psychosocial phenotypes predict short- and long-term treatment response.

The proposed SBIR Phase II program seeks to select a first-in-class, peripherally-restricted, and long-acting somatostatin receptor 4 (LA-SSTR4) agonist clinical candidate for development as a novel non-addictive analgesic able to replace opioids for the treatment of moderate-to-severe chronic pain. The program is based on strong scientific evidence showing that activation of peripheral SSTR4 produces broad spectrum analgesic activity and pursues a unique therapeutic strategy.   Unlike opioids, SSTR4 agonists do not induce constipation, respiratory depression, dependence, addiction, or abuse. Finally, unlike SSTR2 and SSTR5, SSTR4 expression in the pituitary and pancreas is very low, supporting that selective SSTR4 agonists are unlikely to perturb peripheral endocrine functions. The preceding SBIR Phase I program has already established the feasibility of conjugating a short-acting, potent, and selective peptide SSTR4 agonist to the antibody carrier. The resulting LA-SSTR4 agonist lead series has high agonist potency and selectivity for SSTR4 and has demonstrated antinociceptive activity in an animal pain model. The proposed SBIR Phase II program seeks to: optimize the existing lead series and select a clinical candidate for development,  validate and prioritize the indication(s) for clinical development using disease-relevant mouse pain models, and characterize the pharmacokinetics and safety/toxicology profile of the clinical candidate in rat and non-human primates to help design subsequent investigational new drug (IND)-enabling studies.

The chronic low back pain (cLBP) subgroup with comorbid depression or anxiety disorders, known as high negative affect (NA), needs better non-opioid, comprehensive pain treatment options. Data shows that the combination of antidepressants (AD) and fear avoidance physical therapy is more efficacious at improving pain, function, depression, and anxiety in cLBP patients with high NA than each treatment alone or a control condition. Research also finds that an enhanced fear avoidance rehabilitation protocol (EFAR; fear avoidance-based physical therapy, pain education, and motivational messaging) further improves outcomes. To address the unmet needs of cLBP patients with high NA, this study will test in a randomized trial whether the combination of AD and EFAR is more effective than each treatment alone at relieving pain, improving function, combating depression, and preventing opioid misuse. This multimodal combination approach of pharmacotherapy and behavioral therapy is novel to the field and has the potential to shift current treatment paradigms.

Analgesia for post-operative populations remains a significant health need that calls for innovative therapies which improve both safety and outcome measures. Recent FDA drug safety warnings and studies focusing on post-operative analgesia have highlighted the imperative need for new approaches that can be utilized for common clinical scenarios. Accordingly, novel treatment options that are safe and afford additional benefit in relief of pain are needed. In this proposal, the development of an innovative surgical sealant technology is proposed that functions at the level of the surgical wound bed and actively delivers local pharmacologic agents to therapeutically address post-operative pain. New formulations of several analgesic regimens will be assessed for their ability to seal wounds and provide appropriate pain management.

The UCSF Core Center for Patient-centric Mechanistic Phenotyping in Chronic Low Back Pain (UCSF REACH) is an interdisciplinary consortium of basic and clinical scientists dedicated to understanding and clarifying the biopsychosocial mechanisms of chronic low back pain (cLBP). The goal of REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. UCSF REACH has six cores that will support a single research project that is focused on the challenge of developing validated and adoptable tools that enable comprehensive yet routine clinical assessment and treatment of cLBP patients. Overall, the object of REACH is to make optimum use of all available resources to catalyze discovery and translation of novel diagnostics and therapeutics that improve outcomes of cLBP patients.

The Icahn School of Medicine at Mount Sinai (ISMMS) will support the mission of the Early Phase Pain Investigation Clinical Network (EPPIC-Net), through the ISMMS Department of Neurology as the core of a hub and spokes structure. The study contains four specific aims: (1) to streamline and optimize rapid implementation of EPPIC-Net studies, exceeding the required minimum of 100 subjects recruited per year to EPPIC-Net studies; (2) to ensure access to patient populations with a wide range of pain disorders, including CLBP, using a hub and spokes model to ensure effective recruitment; (3) to provide the highest-quality protocol implementation, deep clinical phenotyping of pain disorders, and accurate and complete data collection; and (4) to work collaboratively with the EPPIC-Net Coordinating Centers and investigators from the NIH HEAL Partnership to assist with development/design of clinical trials. The study team will also increase training opportunities through EPPIC-Net within ISMMS and the larger pain research community, training junior investigators to become future pain clinical trials leaders and increase and disseminate knowledge about pain research throughout the network.

Inhibitors of the epigenetic enzymes histone deacetylases (HDACs) produce analgesic responses and are therefore therapeutic targets for pain. The research team recently resolved a PET imaging agent, [11C]Martinostat, that selectively binds to a subset of HDAC enzymes. A series of initial proof-of-concept clinical validation studies will be conducted to evaluate whether [11C]Martinostat PET is a sensitive biomarker to detect the typical (axial) chronic low back pain (cLBP). The research team will validate [11C]Martinostat PET’s ability to differentiate subtypes of pain by comparing axial cLBP and other cLBP patients with radiculopathy and longitudinally study subacute LBP patients (sLBP) to investigate whether there is a unique imaging signature that differentiates patients who develop cLBP and those who recover from low back pain. Using [11C]Martinostat to understand HDAC expression changes in chronic pain patients will validate an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism in developing novel analgesics.

While traditional epidural spinal cord stimulation (SCS) for intractable pain has been very efficacious for the patients responsive to it, the success rate has held at approximately 55%. Dorsal root ganglion (DRG) stimulation has shown promise in early trials to provide greater pain relief. Although the decrease in back pain at 3 months was significantly greater in the DRG arm vs. SCS, the adverse event rate related to the device or implant procedure was significantly higher in the DRG arm. Researchers will develop the “Injectrode” system to make the procedure simpler and safer by using an alternative to implantation: using an injectable pre-polymer liquid composite that cures quickly after injection adjacent to the DRG. They will compare an Injectrode-based system with traditional electrode stimulation at the DRG as an alternative to opioid administration. Researchers will perform benchtop characterization and refinement as a precursor to a clinical study, use modeling and animal testing to refine the efficiency of energy transfer from a transcutaneous electrical nerve stimulation unit to an Injectrode/Injectrode collector concept, and optimize the procedure for the complex anatomy of the human DRG.

An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. Researchers have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, researchers anticipate that their compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions.

Mismanagement of orofacial chronic pain, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, substantially contributes to opioid overuse; overdose-related deaths; and cardiovascular, renal, and neurological complications at epidemic proportions. The current paradigm implies that orofacial conditions could trigger maladaptation of the immune system and plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LT?), members of the tumor necrosis factor superfamily, provide a balance between protective immunity and immunopathology during chronic inflammatory diseases. This project will test the hypothesis that targeting LIGHT and LT? signaling could prevent the development and inhibit the maintenance of chronic pain produced by TMJD and oral cancer, via peripheral mechanisms involving plasticity of immune, stromal, and tumor cells, as well as sensory neurons. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain and offers new therapeutic targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.

The research team developed an in vitro multi-component joint on a chip (microJoint), in which engineered osteochondral complexes, synovium, and adipose tissues were integrated. This study will introduce sensory innervation into the microJoint and a neuron-containing microfluidic ally will be developed to innervate the microJoint. The osteoarthritis (OA) model will be created in the Neu-microJoint system. The research team will assess activation and/or sensitization of nociceptive afferents with electrophysiology, as well as neurite outgrowth. They will mechanically insult the Neu-microJoint and assess the emergence of “pain” in response to prolonged mechanical stress. Researchers will assess the impact of drugs used clinically for management of OA on OA models and will then use “omic” approaches to identify new biomarkers and therapeutic targets. Researchers will assess the impact of opioids—which they hypothesize will increase the rate of joint degeneration and potentiate the release of pain-producing mediators—on neural activity in the presence and absence of joint injury, as well as the integrity of all joint elements.

Validation of novel pain targets is a critical step toward the development of new non-addictive therapeutic agents for chronic pain management. Recent findings suggest that nerve injury-induced concurrent upregulation of the calcium channel alpha-2delta-1 subunit (CaValpha-2-delta-1) and thrombospondin-4 (TSP4) proteins in sensory and spinal cord neurons contributes to neuropathic pain development. Specifically, induction of aberrant excitatory synapse formation and sensitization of neurotransmission in spinal cord underlies this process; accordingly, a target site has been identified in the TSP4 that plays a critical role in mediating these pathological changes upon interaction with the CaValpha-2-delta-1 protein. This project will validate this novel target site in TSP4 for development of non-addictive pain medications, utilizing multidisciplinary approaches to investigate if blocking and genetic deletion of the target site can block or prevent the development of chronic pain state, aberrant excitatory synapse formation, and spinal cord neuron sensitization after injury in multiple rodent neuropathic pain models.